Nanomicellar Formulation for Synergistic Targeting of Prostate Cancer

描述(申请人提供)：前列腺癌(PCa)是美国男性中最常见的恶性肿瘤，也是导致癌症死亡的第二大原因。虽然大多数转移性前列腺癌患者最初对化疗或手术去势有反应，但相当一部分患者最终将发展为激素抵抗型前列腺癌(HRPC)，其有效治疗非常有限。紫杉醇(PTX)是许多治疗HRPC方案的关键成分。然而，PTX的治疗潜力受到相关毒性的限制。此外，大多数接受治疗的患者最终可能会出现耐药性。开发一种策略，同时提高PTX对肿瘤细胞的选择性输送，并使癌细胞对PTX增敏，可能会显著改善结果 对治疗的影响。我们最近开发了一种基于聚乙二醇衍生物的埃姆贝林的新型给药系统。Embelin是一种天然存在的烷基取代羟基苯醌，是Embelia Ribes burm的主要成分。它本身显示出抗肿瘤活性，并使耐药癌细胞对其他化疗药物敏感，在很大程度上彻底阻断了X连锁凋亡蛋白抑制物(XIAP)的活性。像许多其他化学制剂一样，恩贝林的水溶性很差。我们发现，我们团队通过全合成开发的聚乙二醇衍生物灯盏花素形成了小尺寸的胶束(20-30 nm)，并显示出显著增加的溶解度(&gt；200 mg/mL)。更重要的是，PEG-Embelin成为包括PTX和喜树碱在内的其他化合物的高效增溶剂。我们推测，聚乙二醇-恩贝林结合物可以作为一种安全的双功能载体系统，与PTX等联合递送的药物实现相加或协同的抗肿瘤作用。事实上，我们的初步数据显示，通过聚乙二醇-恩贝林胶束传递的PTX在体外和体内都能显著提高抗肿瘤活性。这一应用的重点是检查是否可以通过与Sigma 2受体的小分子配体结合来进一步改善递送系统，Sigma 2受体在包括PCa在内的各种类型的癌症中过度表达。本研究将追求两个具体目标：目标1：确定在PCa特异性纳米胶束中形成的PTX的靶向效率和体内生物分布；目的2：在人PCa动物模型中观察PTX在PCa特异性纳米胶束中的治疗作用。这项研究的成功完成可能会导致开发一种新的疗法来推进前列腺癌的治疗。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most commonly diagnosed malignancy, and the second leading cause of cancer mortality among American males. Although majority of patients with metastatic PCa initially respond to chemical or surgical castration, a significant number will eventually advance to hormone-refractory PCa (HRPC), for which effective treatment is very limited. Paclitaxel (PTX) is a key component of many therapeutic regimens for HRPC. However, the therapeutic potential of PTX is limited by the associated toxicity. In addition, drug resistance may eventually occur in most of the treated patients. Development of a strategy that can simultaneously improve selective delivery of PTX to tumor cells and sensitize the cancer cells to PTX is likely to significantly improve the outcome of the treatment. We have recently developed a novel delivery system that is based on PEG-derivatized embelin. Embelin is a naturally occurring alkyl substituted hydroxyl benzoquinone and a major constituent of Embelia ribes BURM. It shows antitumor activity by itself and sensitizes resistant cancer cells to other chemodrugs largely thorough blocking the activity of X-linked inhibitor of apoptosis protein (XIAP). Like many other chemodrugs, embelin is poorly water soluble. We found that PEG-derivatized embelin, which is developed in our group by total synthesis, forms small-sized micelles (20-30 nm) and shows significantly increased solubility (>200 mg/mL). More importantly, PEG-embelin becomes a highly efficient solubilizing agent for other compounds including PTX and camptothecin. We hypothesize that PEG-embelin conjugates can serve as a safe and dual functional carrier system to achieve additive or synergistic antitumor effect with co-delivered drugs such as PTX. Indeed, our preliminary data showed that delivery of PTX via PEG-embelin micelles led to significant improvement in antitumor activity in vitro and in vivo. This application is focused on examining if the delivery system can be further improved via conjugation with a small molecule ligand for sigma 2 receptor that is overexpressed in various types of cancers including PCa. Two specific aims will be pursued in this proposal: Aim 1: To determine the targeting efficiency and in vivo biodistribution of PTX formulated in PCa-specific nanomicelles; Aim 2: To investigate the therapeutic effect of PTX formulated in PCa-specific nanomicelles in an animal model of human PCa. Successful completion of this study may lead to the development of a novel therapy to advance the treatment of prostate cancer.